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Angelman-Like Syndrome: a Genetic Approach to Diagnosis with Illustrative Cases

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Angelman-Like Syndrome: a Genetic Approach to Diagnosis with Illustrative Cases Hindawi Publishing Corporation Case Reports in Genetics Volume 2016, Article ID 9790169, 6 pages http://dx.doi.org/10.1155/2016/9790169 Case Report Angelman-Like Syndrome: A Genetic Approach to Diagnosis with Illustrative Cases Ho-Ming Luk Clinical Genetic Service, Department of Health, Kowloon, Hong Kong Correspondence should be addressed to Ho-Ming Luk; [email protected] Received 15 December 2015; Revised 14 January 2016; Accepted 14 January 2016 Academic Editor: Christos Yapijakis Copyright © 2016 Ho-Ming Luk. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Epigenetic abnormalities in 15q11-13 imprinted region and UBE3A mutation are the two major mechanisms for molecularly confirmed Angelman Syndrome. However, there is 10% of clinically diagnosed Angelman Syndrome remaining test negative. With the advancement of genomic technology like array comparative genomic hybridization and next generation sequencing methods, it is found that some patients of these test negative Angelman-like Syndromes actually have alternative diagnoses. Accurate molecular diagnosis is paramount for genetic counseling and subsequent management. Despite overlapping phenotypes between Angelman and Angelman-like Syndrome, there are some subtle but distinct features which could differentiate them clinically. It would provide important clue during the diagnostic process for clinicians. 1. Introduction Angelman-like Syndromes actually had alternative genetic diagnoses [6–8] which were important for counseling and Since the first description of Angelman Syndrome (AS) by management. Dr.Angelmanin1965[1],therewasagreatadvancementin Inthisreview,weuse4illustrativecasestoprovidethe understanding of its clinical features and molecular genetic overview of some Angelman-like Syndromes and highlight mechanism. AS is characterized by distinct facial gestalt, their difference with AS, so as to provide some guidance to developmental delay, absent speech, ataxic gait, seizure, and clinicians on the diagnostic workup when they encounter paroxysms of laughter [2]. The incidence reported was about such patients in their practice. 1/12,000 to 1/20,000 [3, 4] without racial predilection. The diagnosis of AS depends on the combination of clinical crite- ria and molecular and/or cytogenetic testing. The consensus 2. Illustrative Cases criteria for clinical diagnosis of AS were proposed in 2006 [5] whichincludedalistofcoreandassociatedfeatures.However, 2.1. Case 1. A 6-month-old girl was referred to genetic clinic the clinical manifestations of AS were highly heterogeneous for developmental delay. She was the second child of noncon- that would overlap with other diseases. Methylation study sanguineous Chinese couple, born at full term with birth on 15q11-13 imprinted region would identify 75–80% of AS weight of 3.83 kg. The perinatal history was unremarkable. that included maternal deletion, paternal uniparental disomy She was noted to have microcephaly (head circumference (UPD), and imprinting center defect. Further analysis of <3thpercentile,bodyweightandbodyheightat75th UBE3A gene would further confirm 10% of cases. How- percentile) and hypotonia at 3 months of age. Investiga- ever, there were still 5–10% of clinically diagnosed AS that tions including metabolic screening, muscle enzyme, and would be rendered “test negative.” With the advancement of computerized tomography of brain were normal. Physical medical genomic technology like array comparative genomic examination at 6 months of age showed microcephaly, flat hybridization (array CGH) and next generation sequencing, occiput, right divergent squint, and hypotonia. No syndromal it was now known that some patients of these “test negative” diagnosis could be ascertained at that time and she was 2 Case Reports in Genetics (a) (b) (c) (d) Figure 1: Facial features of different Angelman-like Syndromes in this series. (a) FOXG1 related disease; (b) Rett Syndrome. (c) Mowat-Wilson Syndrome; (d) Phelan-McDermid Syndrome. ∗ regularly followed up in genetic clinic. She had epilepsy FOXG1{NP 005240.3}:p.[(Gly133Trpfs 68)];[=] which con- since she was 2 years of age and severe global delay at firmed the diagnosis of FOXG1 related congenital variant of developmental assessment. EEG showed nonspecific back- Rett Syndrome. ground slowing, but no epileptiform abnormalities. Brain Magnetic Resonance Image (MRI) showed mild thin- ning of corpus callosum without major structural defect. 2.2. Case 2. A 10-month-old girl was referred to genetic clinic There was no developmental regression, but she devel- for global delay. She was the first child of nonconsanguineous oped stereotypical hand movements (Figure 1), bruxism, Chinese couple, born at 38-week gestation with birth weight andoccasionaloutburstoflaugher.Basedonthecran- of 3.24 kg. Mother had gestational diabetes mellitus that iofacial features like microcephaly, flat occiput, divergent required insulin therapy. She had mild grade bilateral hearing squint, characteristic stereotypical hand movement, and out- impairment and left divergent squint diagnosed at birth. burst of laughter, Angelman/Rett Syndrome was suspected. Onfollow-up,shewasnotedtohavemicrobrachycephaly However, genetic investigations including methylation-spe- and global developmental delay (Figure 1). Brain MRI, cific multiplex ligation-dependent probe amplification (MS- metabolic screening, and array CGH were normal. She had MLPA) for AS, UBE3A gene, MECP2 gene, and array stereotypical handwashing movement since she was 1 year CGH studies were negative. Based on the MRI findings and old. There was no clinical or electrical seizure. Based early onset of microcephaly, FOXG1 related disease was on the craniofacial features like microbrachycephaly, wide suspected. FOXG1 gene test showed a de novo frameshift path- mouth, divergent squint, and behavioral phenotype, AS was ogenic mutation FOXG1{NM 005249.3}:c.[396 397ins26];[=]; initially suspected, but the methylation study and UBE3A Case Reports in Genetics 3 Table 1: Angelman-like Syndrome. Chromatin-remodeling disorder Synaptopathies Unknown mechanism Syndrome Genes Syndrome Genes Syndrome Genes Phelan-McDermid Rett Syndrome/MECP2 duplication MECP2 Syndrome/22q13.3 deletion SHANK3 Pitt-Hopkins Syndrome TCF4 syndrome syndrome Mowat-Wilson Syndrome ZEB2 Christianson Syndrome SLC9A6 Kleefstra Syndrome/9q34.3 deletion EHMT1 HERC2 deficiency HERC2 syndrome MBD5 haploinsufficiency/2q23.1 MBD5 Adenylosuccinase deficiency ADSL deletion syndrome Koolen-de Vries Syndrome/17q23.31 KANSL1 CDKL5 syndrome CDKL5 deletion syndrome Congenital variant of Rett Syndrome FOXG1 MEF2C haploinsufficiency syndrome MEF2C Alpha-thalassemia/intellectual ATRX Ohtahara Syndrome STXBP1 disability syndrome Methylenetetrahydrofolate deficiency MTHFR gene test were negative. Subsequently she had bruxism and during early infancy. Assessment at 1 year and 6 months developmental regression since she was 1 year and 6 months showed that she had moderate to severe grade developmental of age with loss of some motor and social skill. MECP2 study delay with autistic features. Baseline investigations included showed de novo nonsense mutation MECP2{NM 004992.3}: brain MRI and metabolic screening was normal. There was no ∗ c.[808C>T];[=];MECP2 {NP 004983.1}:p.[(Arg270 )];[=]that seizure, regression, or stereotypical hand movement. How- confirmed the diagnosis of Rett Syndrome. ever, she had occasional abnormal outburst of laughter. The head size was normal at 10–25th percentile. Despite the 2.3. Case 3. A5-year-oldgirlwasreferredtogeneticclinicfor fact that she had some behavioral features of AS, overall AS based on the facial dysmorphism. She was the first child clinical profile was not typical (Figure 1). Therefore array of nonconsanguineous Chinese couple, born at full term CGH was performed, which showed a de novo arr[Hg18] with birth weight of 2.9 kg. Perinatal history was unre- 22q13.31q13.33(45,355,784-49,522,658)x1. That means that a markable. She was noted to have dysmorphism and cardiac terminal deletion in chromosome 22 at band q13.31 region murmur during neonatal period. Echocardiogram showed with the size of 4.17 Mb included the SHANK3 gene; thus the patent ductus arteriosus and large secundum atrial septal diagnosis of Phelan-McDermid Syndrome was substantiated. defect. Total corrective operation was done at 1 year of age. Developmental assessment at 2 years of age showed severe 3. Summary and Conclusion grade developmental delay. Stereotypical hand movement, abnormal outburst of laughter, and ataxic gait were developed Loss of maternal inherited UBE3A gene predominantly afterward. Brain MRI showed mild thinning of corpus cal- expressed in the brain was the pathomechanism of AS. losum. Physical examination at genetic clinic showed head Only 90% of clinically diagnosed AS would have identifiable circumference at 3th percentile with body weight and body molecular defect. The remaining 10% were labeled as test neg- height at 10–25th percentile. There was facial dysmorphism, ative Angelman-like Syndrome. These Angelman-like Syn- namely, hypertelorism, medial flared eyebrows, mild over- dromes are actually separate disease entities that are not the hanging columella, pointed chin, and fleshy and uplifted variations of AS. However, due to overlapping clinical phe- earlobes (Figure 1). Based on facial gestalt, Mowat-Wilson notype, their
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